Protein Kinase D1 deletion ameliorates collage-induced arthritis

Abstract

Abstract Although the etiology of Rheumatoid arthritis (RA) is unknown, it is thought that TLR signaling may be involved in the initiation and progression of the disease. Disruption of the TLR signaling at early stages of RA could be a possible therapeutic strategy. We have previously identified protein kinase D1 (PKD1) as an indispensable component in the MyD88-dependent TLR signaling pathway that plays a critical role in acute and chronic inflammation. Although it is currently not known whether PKD1 plays a pathogenic role in RA in humans, we have previously found that daily treatments of a PKC/PKD inhibitor Gö6976 significantly ameliorated arthritic symptoms in collagen-induced arthritis (CIA). Here, we further investigated the role of PKD1 in pathogenesis of CIA in humanized HLA-DR1 transgenic mice using a tamoxifen-inducible PKD1-gene deletion system. We have found that PKD1 deletion resulted in reduced incidence and severity of arthritis in HLA-DR1 mice immunized with type II collagen. In addition, Gr-1+ myeloid lineage cell infiltration into the joint space was significantly reduced and joint destruction (assessed by joint histopathology study and mCT scanning) was ameliorated in the PKD1-deleted mice compared to wild-type. Our results provide evidences that PKD1 might play an important pathogenic role in inflammatory arthritis and that PKD1 could be a new therapeutic molecular target for arthritis.